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Introduction Alzheimer’s Disease (AD) is the most common form of dementia, a general term for serious loss of global cognitive activity in a previously unimpaired person. Symptoms of the neurodegenerative disease include disorientation, mood and behaviour changes, unfounded suspicion of friends and family members, and even difficulty speaking, swallowing and walking. AD is a progressive disease, and its symptoms are known to worsen over a number of years. In many cases the loss of intellectual activity caused by AD is serious enough to interfere with daily life. AD is not a normal part of the aging process. However, the greatest known risk factor is increasing age, and the majority of people diagnosed with the disease are 65 and older (1). AD is physiologically characterized by the loss of neurons and synapses in the cerebral cortex and some subcortical regions. This results in the gross atrophy of the affected regions, typically including the temporal and parietal lobes, as well as the cingulate gyrus and parts of the frontal cortex (2). This severe degeneration of the brain is depicted in''' Figure 1'. Astrocytosis, which refers to an abnormal increase in the number of astrocytes as a result of neurodegenerative disease, is also observed in AD patients (3). Currently, there is no cure for AD, but treatments are available which slow the worsening of symptoms. However, most brain damage and mental decline caused by the disorder is irreversible. Therefore, early diagnosis and treatment of AD prolongs cognitive health (4). An interesting characteristic of AD patients is abnormality in cerebral metabolic function. Specifically, a reduced temporoparietal glucose metabolism has been reported (5). To further investigate cerebral metabolic function in AD patients, Bigl et al. (1999) studied the activities of several glycolytic enzymes (3). Glycolysis is a metabolic pathway that converts glucose – a type of sugar – into two smaller molecules called pyruvate. This is the first major step of cellular respiration, and it occurs in every living cell of every living organism. The net chemical reaction of glycolysis is shown below: As shown in the reaction above, glycolysis yields two molecules of adenosine triphosphate (ATP), which is a high-energy molecule that can later be catabolized to drive energetically unfavourable reactions in the cell forward. Additionally, two pyruvate molecules produced can enter the Citric Acid Cycle to produce more ATP. Understanding the abnormal glycolytic activities in AD patients will allow us to further expand our knowledge of this currently incurable disease. So far, studies regarding glucose metabolism in the brains of AD patients have continued to yield contradictory results. In this review, we will be discussing previously conducted research and analyze the changes in activities of important glycolytic enzymes reported by these studies. Specifically, the specific activities hexokinase, pyruvate kinase, lactate dehydrogenase, and phosphofructokinase will be examined in detail. By objectively critiquing these experiments, we hope to delineate the metabolic processes occuring in the brains of individuals diagnosed with AD. Glycolysis Below is an image map depicting the chemical reactions in glycolysis, as well as the conversion of the final pyruvate molecule to lactate. Enzymes catalyzing each step are labelled. '''Click on one of the four highlighted enzymes (blue)' to further learn about their structure, function in glycolysis, and their activities observed in the brains of patients diagnosed with Alzheimer's disease: Image:Glycolysis_Image_Map.jpg| rect 244 1 436 95 Lactate dehydrogenase rect 130 110 323 203 Pyruvate kinase rect 573 38 768 131 Hexokinase rect 751 314 995 403 Phosphofructokinase desc none Note: Only the enzymes highlighted in blue are the main focus of our project. Conclusion In summary, Bigl et al. found an increase in the specific activity of several glycolytic enzymes in the brains of patients with Alzheimer's disease (3). Though there were no significant changes in hexokinase activity, notable increases were observed in the activities of 6-phosphofructo-1-kinase, pyruvate kinase and lactate dehydrogenase in the frontal and temporal cortex of the brain. In addition, these changes in enzymatic activites were also determined to be correlated with an increased content of glial fibrillary acidic protein, allowing the researchers to further analyze the processes occurring in the diseased organ (3). Previous research has demonstrated signficant decreases in cerebral glucose metabolism in individuals with AD. This suggests that the brains of affected individuals have a lower overall energy requirement, or it could simply mean that their cerebral metabolic capacity is limited (3). Due to a lack of sufficient evidence, it is difficult to interpret these results and arrive at a definite conclusion. Furthermore, many studies have failed to identify the source of reduced glucose uptake in the brains of Alzheimer's patients. The decrease in enzyme activities previously reported also seem to contradict the findings published by Bigl et al. However, they attribute these differences to "improved tissue homogenization and assay conditions" employed in the experiment, suggesting that their results may be a more accurate representation of the true activities of these glycolytic enzymes (3). Based on their findings, Bigl and colleagues propose that two antagonistic processes may be taking place simultaneously in the diseased brains: a decline in glucose metabolism, and reactive gliosis leading to the activation of astrocytes (3). It is believed that the increase in the number of reactive astrocytes is a compensatory response to the neurodegeneration associated with Alzheimer's. Research has shown that AD is often characterized by significant changes in brain plasticity and structure, as well as noticeable neurotrophic effects. It is therefore likely that activated glial cells such as astrocytes are responsible for providing trophic support to surrounding neurons via glia fibrils. This is also supported by previous studies, which found that glial cells are capable of producing and exporting various metabolites to neurons when there is a high demand for energy or reduced availability of glucose. Upregulated GFAP levels, as seen in Bigl et al.'s paper, serve as markers for reactive gliosis. Since the GFAP content was found to be correlated to increased specific activties of PFK, PK, and LDH, the researchers were able to conclude that the observed activation of glucose metabolism was limited to astrocytes in AD brains (3). These astrocytes are capable of interacting and cooperating with surviving neurons nearby, providing fuel in the form of metabolites. In terms of its applications, work in this field could play a crucial role in identifying Alzheimer's disease in susceptible individuals. It may be possible to measure the activities of glycolytic enzymes such as the ones discussed above, and use this data as a criteria for the diagnosis of AD. Though theoretically this seems to be a good indicator of Alzheimer's disease, it is important to remember that there are a large number of studies demonstrating contradictory results. Therefore, further research must be done on this topic to first reach a consensus; only then would this information be useful for diagnosing Alzheimer's disease. ---- [[About_Us|'About the authors.']] Works Cited 1. Brookmeyer, R.; Gray, S.; Kawas, C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998, 88, 1337-1342. 2. Wenk, G. L. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry 2003, 64, 9:7-9:10. 3. Bigl, M.; Bruckner, M. K.; Arendt, T.; Bigl, V.; Eschrich, K. Activities of key glycolytic enzymes in the brains of patients with Alzheimer's disease. J Neural Transm 1999, 106, 499-511. 4. Pryce Roberts, A.; Robertson, N. P. Possible treatment targets in Alzheimer’s disease. J Neurol 2013, 260, 3193-3196. 5. Duara, R.; Grady, C.; Haxby, J. V. Position emission tomography in Alzheimer’s disease. Neurology 1986, 36, 879-887. 6. Garrett, R. H., Grisham, C. M. Biochemistry, 5th ed, 2009, University of Virginia.